In the proposed investigations, we plan to exploit electron microscopic techniques to gain new insights into plasma lipoprotein structure and metabolism. Novel procedures in high resolution electron microscopy will be applied to LDL and HDL structure in order to determine possible surface fine structure and particle symmetry. These procedures will include: 1) protein cross-linking studies in conjunction with electron diffraction, 2) minimal beam irradiation, and, 3) thin carbon substrates. Electron microscopy will be employed in investigations of protein-lipid interaction between apolipoprotein C (or apoA) and triglyceride (with or without added phospholipid). Protein-lipid complexes will be assessed for physiological responsiveness by using them as substrates for LPL and hepatic triglyceride lipase. Degradation products will be identified with the anticipation that we will obtain more cogent insights into chylomicron and VLDL stabilization and degradation. To study interrelationships between lipoprotein classes, we will examine certain metabolic abnormalities including LCAT deficiency and Tangier disease. Attempts will be made to normalize aberrant lipoprotein structures either by incubation with appropriate enzyme or by diet. Ultrastructural changes will be determined and related to lipoprotein function and metabolism. The possible role played by LCAT in the disposal of chylomicron surface material will be tested by studying the effects of LCAT on artificial surface remnants or remnants produced by the action of LPL on native chylomicrons. Smaller, cholesteryl ester-rich lipoprotein species will be looked for in an attempt to understand the relationship between chylomicron and HDL metabolism. Hypercholesteremia is thought to play an active role in atherogenesis and is also associated with the pathology of other lipid dysfunctions such as renal disease and LCAT deficiency. We will study cytological changes produced in the liver and kidney of hypercholesterolemic animal models. Lipid deposition in cells and activity of certain enzymes associated with lipid metabolism will be investigated. These studies are relevant to the broader question of lipid accumulation in atherosclerotic lesions.